Leukocyte is well known to play a critical role in inflammatory reactions that could be caused by microbial intrusion, the damaged tissue or the like. It is also known that leukocytes usually circulate in the blood vessel and, once the tissue is inflamed, leukocytes are infiltrated into the inflamed tissue by passing through the blood vessel wall adjacent to the such a tissue. This infiltration is found to be associated with the integrins expressed on the surface of a leukocyte cell.
An integrin is composed of a heterodimer of glycoprotein in which two noncovalently associated subunits (i.e., α-subunit and β-subunit) coalesce with each other. So far, at least 16 species are known to be included in the family of α-subunit, while at least 9 species are known to be included in the family of β-subunit, and thus these subunits form such a large family, respetively. An integrin “α4β1”, which is known also as VLA-4 (very late antigen-4), is expressed on the cell surface of leukocytes such as monocytes, lymphocytes, eosinophiles, basophiles, mast cells and macrophages (Non-Patent Document 1). VCAM-1 (vascular cell adhesion molecule-1), as well as extracellular proteins such as fibronectin (FN), are known as the ligands of α4β1 (Non-Patent Document 2).
Among the effects obtainable by inhibiting the adhesion between VLA-4 and VCAM-1 are an anti-inflammatory action using an anti-α4 monoclonal antibody (Non-Patent Document 3), inhibitory action against bronchial hyperactivity at the time of antigen induction and inhibitory action against leukocyte infiltration into bronchoalveolar secretion in a guinea pig pulmonary inflammation model using an anti-α4 antibody (Non-Patent Document 4).
Also, there is a report focusing on a suppressive effect on inflammatory diseases by inhibiting the adhesion between VLA-4 and FN (Non-Patent Document 5). According to this report, an artificial CS-1 (connecting segment-1) tripeptide derivative [Phenylacetic acid-Leu(L)-Asp(D)-Phe(F)-d-Pro(d-P)-amide] in the amino acid sequence of CS-1, which is known as a region where binding of FN to VLA-4 occurs, suppressed a rejection reaction in rabbit heart transplantation.
The results of these researches suggest that if the cellular adhesion between VLA-4 and VCAM-1 and/or FN is effectively inhibited, it would be of great use as a means for the treatment of inflammatory diseases. However, any of the low molecular weight compounds, known as having a VLA-4 inhibitory action (Patent Document 1 to Patent Document 7, and Non-Patent Document 6), has yet to be used as a medicament.
Although an orally administrable agents is regarded as preferable in teaching inflammatory diseases, it is also known that most of such compounds have poor oral absorbability and tend to suffer a short retention time in blood. Hence, there are only a few, if any, reports showing that such a sufficient effect has been obtained by oral administration.    [Patent Document 1] WO 02/053534    [Patent Document 2] WO 97/03094    [Patent Document 3] WO 99/23063    [Patent Document 4] WO 99/33789    [Patent Document 5] U.S. Pat. No. 6,355,662    [Patent Document 6] WO 01/000206    [Patent Document 7] WO 01/051487    [Non-Patent Document 1] Helmer, M. Ann. Rev. Immunol., 8, 365 (1990)    [Non-Patent Document 2] Elices, et al., Cell, 60, 577 (1990)    [Non-Patent Document 3] Lobb R. R., et al., J. Clin., Invest., 94, 1722-28 (1994)    [Non-Patent Document 4] Pretolani, et al., J. Exp. Med., 180, 795 (1994)    [Non-Patent Document 5] Molossi et al., J. Clin. Invest., 95, 2601 (1995)    [Non-Patent Document 6] Jefferson W. Tilley and Achyutharao Sidduri, Drugs of the Future, 26(1), 985-998 (2001)